Abstract

Diabetic patients who attempt strict management of blood glucose levels frequently
experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and
cognitive impairment. There is no effective tool for prevention of these unwanted
clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been
recognized as an anti-inflammatory and neuroprotective agent in several animal models
such as stroke and traumatic brain injury. In the present study, we tested whether
minocycline also has protective effects on hypoglycemia-induced neuronal death and
cognitive impairment. To test our hypothesis we used an animal model of insulin-induced
acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose
reperfusion and injected once per day for the following 1 week. Histological evaluation
for neuronal death and microglial activation was performed from 1 day to 1 week after
hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial
activation began to be evident in the hippocampal area at 1 day after hypoglycemia
and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced
microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was
significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia.
Hypoglycemia-induced cognitive impairment is also significantly prevented by the same
minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore,
these results suggest that delayed treatment (6 hours post-insult) with minocycline
protects against microglial activation, neuronal death and cognitive impairment caused
by severe hypoglycemia. The present study suggests that minocycline has therapeutic
potential to prevent hypoglycemia-induced brain injury in diabetic patients.